Diseases of the temporomandibular joint (TMJ) are of complex etiopathology associated with progressive inflammation and cartilage destruction. Physical therapies such as continuous passive motion yield beneficial effects on inflamed TMJs by an as-yet-unknown mechanism, but one that is likely to involve mechanical activation of chondrocytes. Since inflammatory cytokines like IL-1beta play a major role in cartilage destruction, it is our hypothesis that the beneficial effects of mechanical strain are anti-inflammatory in nature. Furthermore mechanical strain exerts its effects by suppressing IL-lbeta-induced activation of transcription factors. This in turn positively or negatively affects IL-1-induced transcriptional regulation. This is based on the Principal Investigator's recent observations that, in vitro, cyclic tensile strain (CTS) suppresses IL-1-dependent mRNA transcription of multiple proteins that induce cartilage destruction such as, inducible nitric oxide synthase, cyclooxygenase-II and collagenase. In addition CTS abrogates IL-lbeta-induced suppression of tissue inhibitor of metalloprotease-II synthesis and thereby limits cartilage matrix destruction. These observations suggest that CTS acts on the signal transduction cascade of IL-beta upstream of mRNA transcription. Furthermore, these findings are of clinical relevance in that the effects of CTS on TMJ chondrocytes are observed at concentrations of IL-1beta similar to those present in synovial fluids from inflamed TMJs. Although mechanical strain is known to exert definitive signals on cellular metabolism, how these signals are transduced in cells is largely unknown. In this application studies are proposed to characterize specific mechanisms by which mechanical strain suppresses the destructive effects of inflammatory mediators in TMJ diseases. IL-1-activated chondrocytes are the first cells that provide defined CTS responses, which can be evaluated at the transcriptional level and related to gene activation. These cells are thus ideally suited for systematic examination of mechanisms of CTS mediated signal transduction, specifically those that suppress the inflammatory actions of IL-1beta. Utilizing this system the Principal Investigator proposes to: (1) examine the effects of CTS on receptor activation by assessing activation of IL-lR-associated kinase; (2) identify CTS-mediated signals that may inhibit IL-1beta-induced activation of NF-kB by assessing the activation of MAP kinases upstream of I-kB (inhibitor of NF-kB), including I-kB kinases, IKKalpha and IKKbeta; (3) identify CTS mediated signals that may inhibit the IL-1beta induced nuclear translocation of NF-kB, and the subunit structure of NF-kB involved in the anti-inflammatory responses of CTS. The results of these investigations will be critical in unveiling novel pathways used during anti-inflammatory actions of CTS that can be exploited for the development of therapeutic interventions to limit or reverse the catabolic effects of inflammatory cytokines in TMJ diseases.